nutrients
Review
Potential of Creatine in Glucose Management and Diabetes
Marina Yazigi Solis, Guilherme Giannini Artioli
and Bruno Gualano *
Applied Physiology & Nutrition Research Group, School of Medicine, University of Sao Paulo,
Sao Paulo 01246-903, Brazil; marina.solis@gmail.com (M.Y.S.); artioli@usp.br (G.G.A.)
* Correspondence: gualano@usp.br; Tel.: +55-11-3061-8789
Abstract: Creatine is one of the most popular supplements worldwide, and it is frequently used by
both athletic and non-athletic populations to improve power, strength, muscle mass and performance.
A growing body of evidence has been identified potential therapeutic effects of creatine in a wide
variety of clinical conditions, such as cancer, muscle dystrophy and neurodegenerative disorders.
Evidence has suggested that creatine supplementation alone, and mainly in combination with exercise
training, may improve glucose metabolism in health individuals and insulin-resistant individuals,
such as in those with type 2 diabetes mellitus. Creatine itself may stimulate insulin secretion in vitro,
improve muscle glycogen stores and ameliorate hyperglycemia in animals. In addition, exercise
induces numerous metabolic benefits, including increases in insulin-independent muscle glucose
uptake and insulin sensitivity. It has been speculated that creatine supplementation combined with
exercise training could result in additional improvements in glucose metabolism when compared
with each intervention separately. The possible mechanism underlying the effects of combined
exercise and creatine supplementation is an enhanced glucose transport into muscle cell by type
4 glucose transporter (GLUT-4) translocation to sarcolemma. Although preliminary findings from
small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of
creatine for improving glycemic control is yet to be confirmed. In this review, we aim to explore the
possible therapeutic role of creatine supplementation on glucose management and as a potential
anti-diabetic intervention, summarizing the current knowledge and highlighting the research gaps.
Citation: Solis, M.Y.; Artioli, G.G.;
Gualano, B. Potential of Creatine in
Keywords: dietary supplements; exercise; skeletal muscle; glycemic control; type 2 diabetes mellitus
Glucose Management and Diabetes.
Nutrients 2021, 13, 570. https://
doi.org/10.3390/nu13020570
1. Introduction
Academic Editor: Richard B. Kreider
Received: 22 January 2021
Accepted: 3 February 2021
Published: 9 February 2021
Publisher’s Note: MDPI stays neutral
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Copyright: © 2021 by the authors.
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distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, imposing
high health costs for public and private health systems. According to the Global Burden
of Disease Study, diabetes incidence increased from 11.3 million in 1990 to 22.9 million in
2017, whilst prevalence increased from 211.2 million in 1990 to 476.0 million in 2017 [1].
In 2017, the International Diabetes Federation estimated that 451 million adults live with
diabetes, and by 2045, this number could increase to 693 million if no preventive measures
are adopted [2].
T2DM is a metabolic disorder characterized by sustained hyperglycemia resulting
from impaired insulin production by pancreatic β cells, impaired insulin action (i.e., insulin
resistance), or both [3]. Chronic hyperglycemia in diabetes is associated with several
cardiometabolic disorders, such as hypertension, dyslipidemia, atherosclerosis and visceral
obesity. Moreover, T2DM is considered one of the top 10 causes of premature deaths from
noncommunicable diseases, and is associated with increased mortality from infections,
cardiovascular disease, stroke, chronic kidney disease, chronic liver disease, and cancer. In
fact, all-cause mortality risk increases by 2- to 3-fold in individuals with diabetes [1].
T2DM can be managed with non-pharmacological treatment (i.e., weight reduction,
dietary intervention, and physical activity) and/or pharmacological treatment [4]. There
have been several dietary candidates to help control glycemia, so far with little or no
clinical support from large, controlled trials. In the past two decades, creatine (α-methyl
Nutrients 2021, 13, 570. https://doi.org/10.3390/nu13020570
https://www.mdpi.com/journal/nutrients
Nutrients 2021, 13, 570
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guanidine-acetic acid) supplementation has also been speculated as a dietary supplement
potentially able to improve glucose control and insulin resistance.
Creatine is a naturally occurring amine, which is endogenously synthesized (~1 g·d−1 )
in the liver, kidneys and pancreas from the amino acid glycine, methionine and arginine.
Creatine can also be exogenously obtained from food sources (~1–5 g·d−1 ), especially by
the ingestion of beef, pork, chicken and fish. In humans, creatine is found in its free (60
to 70%) and phosphorylated (30 to 40%) forms. Approximately 95% of the total bodily
creatine store is found in skeletal muscle, with the remaining 5% being found in cells with
rapid energy demands, such as cardiac myocytes, retina, neurons and testicles. Creatine
excretion occurs through its irreversible and non-enzymatic conversion to creatinine, which
is then eliminated by the kidneys [5].
Creatine supplementation is a popular strategy to improve exercise performance in
healthy individuals and athletes due to its efficacy of increasing muscle free creatine and
phosphorylcreatine contents [6]. Strong evidence indicates that creatine supplementation
increases muscle strength, lean mass and improve performance in high-intensity, shortduration exercise [7]. Moreover, new applications for creatine have been proposed, as
creatine seems to have potential therapeutic properties in a wide variety of clinical conditions, such as muscle disorders, neurodegenerative conditions and, metabolic dysfunctions,
including insulin resistance and T2DM [8].
There is preliminary evidence showing that creatine supplementation could affect
glucose metabolism. Studies have demonstrated that creatine ingestion combined with
carbohydrate promote greater total muscle glycogen accumulation in animals [9,10] and in
humans [11]. Additionally, creatine supplementation along with carbohydrate promotes
greater muscle creatine retention than creatine alone [12]. These effects may be partially
explained by the fact that both muscle glucose and creatine uptake are influenced by
insulin-dependent transporters. In vitro studies showed that creatine increases insulin
secretion [13,14]; human studies, however, did not demonstrate the same effects [15,16]. In
addition, creatine supplementation was shown to ameliorate hyperglycemia in transgenic
Huntington mice and delay diabetes offset [17]. In humans, creatine supplementation associated with exercise training improved glycemia in sedentary [18] and T2DM adults [19].
Altogether, these findings provide the rationale for exploring the application of creatine as
a potential anti-diabetic intervention. In this short, narrative review, we will describe the effects of creatine supplementation on glycemic control, summarizing the current knowledge
and highlighting the research gaps.
2. Insulin resistance in the Context of the Interplay between Creatine and
Glucose Metabolism
Under normal conditions, insulin is secreted by pancreatic β cells in response to the
presence of energy substrates (e.g., glucose, fatty acids and amino acids), hormones and
changes in energetic demands (e.g., fasting–feeding cycle, exercise and stress) in order
to maintain normal blood glucose levels [3]. Insulin binds to its tyrosine kinase-type
receptor and activates phosphorylation of a family of insulin receptor substrates (IRSs),
especially IRS1 and IRS2 [20]. IRS-phosphorylated proteins bind and activate intracellular
signaling molecules, such as phosphatidylinositol 3 kinase (PI3K), which in turn, promotes
the translocation of the type 4 glucose transporter (GLUT-4) to the plasma membrane,
ultimately resulting in the uptake of bloodstream glucose into the muscle skeletal [3].
Additionally, insulin stimulates the mitogen-activated protein kinase (MAPK) pathway, a
necessary step in cell proliferation and nuclear activation [21].
Insulin resistance is a condition that precedes T2DM and, together with genetic and
environmental factors, such as obesity and physical inactivity, may lead to the failure
of β-cell function and, hence, a progressive decline in insulin secretion [22,23]. Insulin
resistance is generally associated with suppressed PI3K pathway, with increased serine
phosphorylation of IRS proteins and inhibited tyrosine phosphorylation [24]; IRS protein
degradation also seems to occur in some conditions [25]. Additionally, insulin resistance in
Nutrients 2021, 13, x FOR PEER REVIEW
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mic control in T2DM patients were linked to increased GLUT-4 translocation to the sarcolemma, but not to changes in total muscle GLUT-4 content [19]. Increased GLUT-4 translocation was also associated with increased Adenosine Monophosphate-activated protein
kinase
(AMPK-α)
a protein
in GLUT-4
translocation
[38]. Likewise,
T2DM
could
displayexpression,
a suboptimal
GLUT-4involved
translocation,
irrespective
of decreased
muscle
amongcontent
healthy[19].
young men, short-term creatine supplementation upregulated protein kiGLUT-4
nase
Bα (PKBa/Akt1),
a protein
that plays
a role in
the insulin-stimulated
GLUT-4
transRecent
evidence has
suggested
that T2DM
individuals
display altered
creatine
metabolism
[26,27].
In a prospective
location and
in glycogen
synthesis cohort
[34]. study including more than 4700 participants,
Post etExercise
al. [27] observed
that
higher plasma
was associated
with
knowingly
modulates
musclecreatine
glucose concentration
uptake by increasing
(1) extracellular
increased
of T2DM.
themuscle
authors,
higher extracellular
creatineand
con-(3)
glucose incidence
delivery, from
bloodAccording
to muscle,to(2)
membrane
glucose transport,
centration
and lower
intracellular
phosphorylcreatine/creatine
may be related
to anpaintracellular
glucose
phosphorylation
and insulin sensitivitycontent
[40]. Importantly,
T2DM
impaired
intracellular
energy
state that
suggests mitochondrial
dysfunction,
a postulated
tients retain
the capacity
of GLUT4
translocation
to the sarcolemma
in response
to exercise
mechanism
in T2DMa pathophysiology
[27]. Whether
creatine
is either
a marker
[41], whichinvolved
makes exercise
potent means to improve
glucose
uptake.
Exercise-induced
orGLUT-4
maker intranslocation
this process seems
remains
be addressed.
to to
occur
via AMPK pathway in an insulin-independent manThe
potential
basis
for
creatine
supplementation
to improve
glycemic
control
involves:
ner [42]. Thus, irrespective of circulating insulin levels
or peripheral
insulin
action
(which
(1)iscreatine-induced
increased
insulin
secretion;
(2)
creatine-induced
changes
in
osmoregfacilitated trough muscle contraction via improvements in insulin signaling), exercise
ulation,
and (3)
creatine-induced
glucose uptake
via an augment
in improving
GLUT-4
can directly
induce
a substantive increased
GLUT-4 translocation
to sarcolemma,
thereby
content
and/or
translocation.
In addition,
exerciseevidence
training has
been that
suggested
to has
havethe
glycemic
control
[43]. Of relevance,
preliminary
suggests
creatine
synergistic
effects
to
creatine,
leading
to
the
assumption
that
these
combined
interventions
potential to enhance the well-known beneficial effects of exercise on glucose control. The
could
greater
benefits in glycemic
vs. creatinewith
or exercise
alone
[28]. The
role foster
of creatine
supplementation,
alone control
or in combination
exercise,
on glucose
mepotential
mechanisms
that
could
explain
the
potential
benefits
of
creatine,
associated
or
tabolism is compressively covered in the next two subsections.
not with exercise, on glucose control are illustrated in Figure 1.
Figure
1. Possible
creatine-related
mechanisms
on glycemic
control.
Potential
mechanisms
underpinning
the role
creatine
Figure
1. Possible
creatine-related
mechanisms
on glycemic
control.
Potential
mechanisms
underpinning
theof
role
of creaontine
glucose
metabolism
involve:
(1)
increased
beta-cell
insulin
secretion;
(2)
improved
water
retention
and
osmosensing
on glucose metabolism involve: (1) increased beta-cell insulin secretion; (2) improved water retention and osmosensgenes
and (3)
increased
glucose
uptake
via type
4 glucose
transporter
(GLUT-4)
content
andand
activity.
Additionally,
(4)(4)
ing genes
and
(3) increased
glucose
uptake
via type
4 glucose
transporter
(GLUT-4)
content
activity.
Additionally,
creatine
supplementation
could
enhance
thethe
known
benefits
of of
exercise
on on
glucose
uptake/insulin
sensitivity.
There
areare
creatine
supplementation
could
enhance
known
benefits
exercise
glucose
uptake/insulin
sensitivity.
There
currently
insufficient
clinical
data
support
these
mechanisms.
Note:
creatine;
CreaT:
creatine
transporter;
currently
insufficient
clinical
data
to to
support
allall
of of
these
mechanisms.
Note:
Cr:Cr:
creatine;
CreaT:
creatine
transporter;
IR:IR:
insulin
receptor;
GLUT-4:
glucose
transporter;
PKBa/Akt1:
protein
kinase
Bα;
AMPK:
Adenosine
Monophosphate-actiinsulin receptor; GLUT-4: glucose transporter; PKBa/Akt1: protein kinase Bα; AMPK: Adenosine Monophosphate-activated
vatedkinase.
protein kinase.
protein
3. Effects
of Creatine
Supplementation
Alone on
Glycemic
In relation
to the effects
of creatine on insulin
secretion,
HillControl
et al. [29] were the first to
show, in
dogs, that
an acute dose of
creatineintermuscular
resulted in hypoglycemia.
in by
vitro
Creatine
supplementation
increases
total creatineLater,
content
10 studto 30%
iesinconfirmed
supraphysiological
creatine
concentrations
elicited aindicates
modest stimulation
children, that
adults
and older individuals
[6,44].
Clinical evidence
that creatine
ofsupplementation
insulin secretion improves
in isolatedfat-free
rat pancreas
[14].delays
Similarfatigue,
resultsincreases
were shown
in exstrength
vivo
mass [34],
muscle
experiments with mouse islets [13] and with insulinoma cells [30]. In pre-clinical studies
involving different animal models, creatine supplementation increased circulating insulin
Nutrients 2021, 13, 570
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levels [31] and improved insulinogenic index in T2DM rats [32]. However, human studies
involving healthy [18] and T2DM adults [19] did not show increased insulin secretion
either when creatine was provided alone or in combination with exercise training [19,33].
Creatine is also able to promote muscle water retention, thereby leading to changes
in cell osmolarity [34]. Increased intracellular osmolarity induces cellular swelling, which
may activate cell-volume sensitive signaling cascades capable of inducing adaptive changes
in intra- and extracellular osmolarity. It is well documented that cell swelling is a potent
stimulus to glycogen synthesis in muscle [35] and liver [36]. Thus, creatine-induced cell
swelling could improve muscle glycogen stores. In fact, 10 days of creatine supplementation
in health adults was able to increase glycogen stores and modulate mRNA content of genes
and protein content involved in osmosensing, which could stimulate anabolic signal
transduction, such as myogenin and, consequently, satellite cell activation [34]. In addition,
increased intracellular osmolarity were associated with increases in circulating IGF-1,
which promotes insulin-like effects and decreases counterregulatory hormones [37], which
are involved in glycogen catabolism.
Some studies have suggested that oral creatine supplementation holds potential to
promote muscle glucose uptake [9,19,38]. GLUT-4 is a key protein involved in transmembrane glucose transport and glucose uptake by skeletal muscle cells [39]. Increases in
membrane GLUT-4 content could ultimately result in improved insulin sensitivity and
glucose tolerance [9]. In rodents, creatine has been shown to increase SLC2A4 (GLUT-4)
gene expression and to enhance GLUT-4 protein content in muscle [10]. Similar effects have
also been reported in humans after creatine supplementation accompanied by an exercise
training program following limb immobilization [9], although not all studies have found
the same outcomes [33,34]. Interestingly, creatine-induced improvements on glycemic
control in T2DM patients were linked to increased GLUT-4 translocation to the sarcolemma,
but not to changes in total muscle GLUT-4 content [19]. Increased GLUT-4 translocation
was also associated with increased Adenosine Monophosphate-activated protein kinase
(AMPK-α) expression, a protein involved in GLUT-4 translocation [38]. Likewise, among
healthy young men, short-term creatine supplementation upregulated protein kinase Bα
(PKBa/Akt1), a protein that plays a role in the insulin-stimulated GLUT-4 translocation
and in glycogen synthesis [34].
Exercise knowingly modulates muscle glucose uptake by increasing (1) extracellular
glucose delivery, from blood to muscle, (2) muscle membrane glucose transport, and (3)
intracellular glucose phosphorylation and insulin sensitivity [40]. Importantly, T2DM
patients retain the capacity of GLUT4 translocation to the sarcolemma in response to
exercise [41], which makes exercise a potent means to improve glucose uptake. Exerciseinduced GLUT-4 translocation seems to occur via AMPK pathway in an insulin-independent
manner [42]. Thus, irrespective of circulating insulin levels or peripheral insulin action
(which is facilitated trough muscle contraction via improvements in insulin signaling),
exercise can directly induce a substantive GLUT-4 translocation to sarcolemma, thereby
improving glycemic control [43]. Of relevance, preliminary evidence suggests that creatine
has the potential to enhance the well-known beneficial effects of exercise on glucose control.
The role of creatine supplementation, alone or in combination with exercise, on glucose
metabolism is compressively covered in the next two subsections.
3. Effects of Creatine Supplementation Alone on Glycemic Control
Creatine supplementation increases intermuscular total creatine content by 10 to 30%
in children, adults and older individuals [6,44]. Clinical evidence indicates that creatine
supplementation improves fat-free mass [34], delays fatigue, increases muscle strength
and, particularly in older adults, improves performance in activities of daily living [45–47].
Additionally, creatine supplementation upregulates genes and protein content of kinases
involved in osmosensing and signal transduction, cytoskeleton remodeling, protein and
glycogen synthesis regulation, satellite cell proliferation and differentiation [34]. Therefore,
Nutrients 2021, 13, 570
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even without exercise, creatine alone seems to modulate skeletal muscle signaling, leading
to potential short-term, physiological adaptations.
A study with animals revealed that 3 weeks of creatine administration (2% of the diet)
significantly increased muscle glycogen stores possibly due to upregulation of GLUT-4
expression and AMPK phosphorylation in female Wistar rats [10]. Moreover, Rooney
et al. [31] showed increased plasma insulin concentrations in Wistar male rats supplemented with creatine (2% of the body weight) for eight weeks. The authors attributed this
result to increased pancreatic total creatine content, which may have altered insulin secretion. In contrast, Op’t Eijnde et al. [9] reported that creatine intake (5 g·kg−1 ·d−1 of creatine
for 5 days) in Wistar male rats did not increase GLUT-4 expression or enhance the sensitivity and the responsiveness of rat muscles to insulin. Similarly, Young and Young [48]
did not find changes in glucose metabolism following creatine intake (300 mg·kg−1 ·d−1 of
creatine over 5 weeks) in Sprague Dawley rats.
Creatine supplementation has been tested in different experimental paradigms of
insulin resistance. Ferrante et al. [17] studied the effects of creatine ingestion in transgenic
mice model of Huntington’s disease. Different doses of creatine (1, 2, or 3%) resulted in
a substantial neuroprotective effect, improvement in the rotarod test performance and
a significant reduction in hyperglycemia that typically accompanies this experimental
model. Interestingly, the administration of creatine also delayed the onset of diabetes in
these mice. In addition, Op’t Eijnde et al. [32] supplemented Goto-Kakizaki rats, a T2DM
model, with creatine (2% of the diet) for eight weeks, and showed an improvement in
the insulinogenic index (plasma glucose and insulin ratio), which was mostly attributed
to a reduction in insulinemia. The authors concluded that creatine supplementation was
able to improve insulin sensitivity in skeletal muscle of insulin-resistant rats. In contrast,
using an animal model of severe muscle wasting and insulin resistance induced by highdose dexamethasone, Nicastro et al. [49] showed that 7 days of creatine supplementation
(5 g·Kg−1 ·d−1 of creatine) aggravated hyperglycemia and hyperinsulinemia in male Wistar
rats. These findings highlight the complexities in interpreting and generalizing data
obtained from creatine studies involving animal models, since there is a large speciespecific variability in response to creatine supplementation. This makes it difficult to
reconcile pre-clinical data involving creatine [50]. The studies assessing the effect of
creatine supplementation alone on glycemic control in animal models are summarized in
Table 1.
Table 1. Effect of creatine supplementation alone in glucose metabolism in animals.
Reference
Model
Creatine Protocol
Ferrante et al. [17]
Transgenic mice model
of Huntington’s disease
Diet supplemented with 1,
2, or 3% of Cr for 21 d
Op’t Eijnde et al. [9]
Male Wistar rats
Powdered rat chow with
5% of Cr for 5 d
Young and Young, [48]
Male Sprague
Dawley rats
300 mg·kg−1 ·d−1 for 5 wk
Rooney et al. [31]
Male Wister rats
Chow containing 2% of Cr
for 2, 4, or 8 wk
Main Findings
↑ glucose tolerance;
↑ neuroprotective effect;
↑ body weight;
↑ motor performance on the rotarod test.
↑ Cr and PCr muscle content;
↔ muscle GLUT-4 content;
↔ glucose transport rate;
↔ plasma insulin;
↔ blood glucose.
↑ Cr and PCr muscle content;
↔ basal rates of glucose uptake;
↔ insulin-stimulated rates of glucose uptake.
↔ fasting plasma glucose;
↔ plasma glucose after oral glucose load;
↑ fasting plasma insulin levels;
↑ pancreatic TCr content.
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Table 1. Cont.
Reference
Model
Creatine Protocol
Ju et al. [10]
Female Wistar rats
Chow containing 2% of Cr
for 3 wk
Op’t Eijnde et al. [32]
Male Goto-Kakizaki rats
Pallets enriched with 2%
of Cr for 8 wk
Nicastro et al. [49]
Male Wistar rats
5 g·Kg−1 ·d−1 of Cr for 7 d
+
5 mg·kg−1 ·d−1 of DXM
Main Findings
↑ glycogen content;
↑ muscle GLUT-4 content;
↑ GLUT-4 mRNA;
↑ AMPK phosphorylation;
↑ Acetyl-Coa carboxylase phosphorylation.
↑ muscle Cr content only in young rats (but not
in older rats);
↓ plasma insulin concentration;
↔ Blood D-glucose concentration after OGTT;
↓ insulinogenic index.
↑ serum glucose and insulin after Cr + DXM;
↑ HOMA-IR after Cr + DXM;
↓ GLUT-4 translocation after Cr + DXM
Notes: ↑: increase; ↓: decrease; ↔: no change; Cr: Creatine; PCr: phosphorylcreatine; TCr: total creatine; OGTT: oral glucose tolerance test;
GLUT-4: glucose transporter; AMPK: AMP-activated protein kinase; HOMA-IR: Homeostatic Model Assessment for Insulin Resistance (a
surrogate of insulin resistance); DXM: dexamethasone.
In humans, creatine supplementation (5 g·d−1 of creatine for 42 days) induced an
increase in plasma glucose in response to an oral glucose load in health vegetarians
adults [51]. Van Loon et al. [33] demonstrated that creatine supplementation alone (20 g·d−1
for 5 days followed by 2 g·d−1 for 6 weeks) increased glycogen content (+18%) in young,
non-vegetarian adults. In contrast, Newman et al. [16] showed that creatine supplementation (20 g·d−1 for 5 days followed by 3 g·d−1 for 28 days) did not influence muscle glycogen
content, plasma glucose and insulin responses during an oral glucose tolerance test in
healthy, active, male adults. Additionally, insulin sensitivity surrogates (i.e., glucose-insulin
index and index of insulin sensitivity) did not change with creatine ingestion, indicating
that insulin action and secretion remained unaltered [16].
Van Loon et al. [33] showed no effect of creatine on GLUT-4 mRNA and GLUT-4
protein content. Similarly, Safdar et al. [34] conducted a microarray analysis and did
not observe changes in GLUT-4 mRNA after creatine supplementation (20 g·kg−1 ·d−1
for 3 days followed by 5 mg·kg−1 ·d−1 for 7 days) in young, healthy men. Nevertheless,
they observed an increase in PKBa/Akt1 mRNA, which participates in glycogen synthesis
via increasing glycogen synthase activity. The authors also showed a 21% decrease in
skeletal muscle phosphofructokinase and glycogen phosphorylase mRNA, suggesting that
creatine supplementation in the absence of exercise could eventually increase muscle
glycogen stores by increasing the cascade signaling leading to GLUT-4 recruitment to the
sarcolemma, despite the lack of changes in GLUT-4 [34]. In a significant different model,
however, creatine supplementation (20 g·d−1 for 2 weeks) was shown to prevent the drop
in GLUT-4 protein expression induced by leg immobilization in healthy young men (+9%
in the creatine group vs. −20% in the placebo group) [9]. In an open-label, cross-over
study (with a 2-day washout period) involving a small sample of T2DM patients, creatine
supplementation (6 g·d−1 for 5 days) was as effective as metformin (2 × 500 mg·d−1 ), a
widely used anti-diabetic drug, in lowering blood glucose concentrations [52]. The human
studies assessing the effect of creatine supplementation alone on glycemic control are
summarized in Table 2.
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Table 2. Effect of creatine supplementation alone in glucose metabolism in humans.
Reference
Sample (n)
Study Design
Creatine Protocol
Main Findings
↑ muscle TCr;
↔ muscle glycogen content;
↔ plasma glucose and insulin
during OGTT;
↔ glucose-insulin index;
↔ index of insulin sensitivity.
↑ plasma total Cr
concentration;
↑ plasma glucose response;
↔ plasma insulin.
↑ muscle glycogen, Cr and PCr
after loading phase, with a
decline in maintenance phase;
↔ GLUT-4
mRNA;
↔ total muscle GLUT-4
protein content.
↑ muscle total Cr
↑ PKB/Akt1 expression and
protein;
↑ MAPK expression;
↔ GLUT-4
mRNA
↓ glucose concentration in both
groups;
↔ insulin, C-peptide and,
HbA1c.
Newman et al. [16]
Healthy, active,
untrained, male
adults (17)
Sigle-blind,
placebo-controlled trial
Loading phase:
20 g·d−1 (4 × 5 g) of
Cr for 5 d
+
Maintenance phase:
3 g·d−1 for 28 d
Rooney et al. [51]
Healthy, vegetarian
adults (14)
Controlled-trial
5 g·d−1 of Cr for 42 d
Double-blind
placebo-controlled trial
Loading phase:
20 g·d−1 (4 × 5 g) of
Cr for 5 d
+
Maintenance phase:
2 g·d−1 for 6 wk
Double-blind,
crossover, randomized,
placebo-controlled trial
Loading phase:
20 g·d−1 (4 × 5 g) of
Cr for 3 d
+
Maintenance phase:
5 g·d−1 for 7 d
Open-label, cross-over
6 g·d−1 of Cr or
1000 mg·d−1 of
metformin for 5 d
Van Loon et al. [33]
Young,
nonvegetarians
adults (20)
Safdar et al. [34]
Young, healthy,
nonobese men (12)
Rocic et al. [52]
Recently diagnosed
T2DM patients,
without anti-diabetic
treatment (30)
Notes: ↑: increase; ↓: decrease; ↔: no change; Cr: Creatine; PCr: phosphorylcreatine; TCr: total creatine; GLUT-4: glucose transporter;
OGTT: oral glucose tolerance test; HbA1c: glycosylated hemoglobin; Akt1: protein kinase B; MAPK: mitogen-activated protein kinases.
4. Effects of Creatine Supplementation Combined with Exercise on Glycemic Control
Exercise has been recognized as a cornerstone in diabetes management, in addition
to diet and hypoglycemic/antihyperglycemic agents. Regular physical activity induces
beneficial metabolic and hemodynamic changes, resulting in improvements in insulinindependent muscle glucose uptake and in insulin sensitivity, as well as increased glycogen
content [39,53]. The benefits of exercise as regard to glucose metabolism are widely reported in trained and untrained healthy [54], obese [55], insulin-resistant [56] and T2DM
individuals [57]. Creatine supplementation has emerged as a strategy capable of enhancing
the physiological and metabolic adaptations to exercise, which could confer protection
in insulin resistance conditions [19,28,58]. Data supporting this hypothesis are so far
inconclusive, however.
Souza et al. [59] showed that oral creatine administration (5 g·kg−1 ·d−1 for 7 days
followed by 1 g·kg−1 ·d−1 for 8 weeks), associated or not with high-intensity swimming
training, reduced plasma glucose levels in Wistar rats. Similarly, Araujo et al. [60] demonstrated that Wistar rats receiving creatine supplementation (diet supplemented with 13%
for 7 days followed by 2% for 55 days) plus high-intensity exercise training exhibited a
smaller area under the curve for glucose in response to an oral glucose challenge. On the
other hand, Freire et al. [61] did not show any effect of creatine (2% of creatine in drinking
water for 8 weeks) plus swimming training on plasma glucose responses to an oral glucose
tolerance test in Wistar rats. Likewise, Vaisy et al. [62] did not demonstrate any benefits
of creatine supplementation (diet enriched with 2.5% of creatine for 12 weeks) alone or in
combination with exercise training on glucose homeostasis and muscular insulin sensitivity
in Wistar rats with insulin resistance induced by a sucrose-rich cafeteria diet.
These conflicting results could be partially explained by the differences in creatine
supplementation regimen and exercise types. For instance, both Freire et al. [61] and
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Vaisy et al. [62] used a single-phase creatine protocol throughout the entire intervention
period, whereas others opted for a loading dose followed by a maintenance phase [62,63].
Training models also varied considerably with the use of treadmill [59,61,62] and swimming
exercises [60], which precludes more direct comparisons concerning the exercise stimuli
to which the animals were subjected. Therefore, the overall conclusions from pre-clinical
studies are equivocal. The studies assessing the effects of creatine supplementation along
exercise on glycemic control in animals are summarized in Table 3.
Table 3. Effect of creatine supplementation along with exercise in glucose metabolism in animals.
Reference
Model
Creatine and Training Protocol
Loading phase:
5 g·kg−1 body weight of Cr for 7 d
+
Maintenance phase: 1 g·d−1 for 8 wk
Training: swimming
Pallets enriched with 2% of Cr for 4 or 8
wk
Training: swimming
Souza et al. [59]
Male Wistar rats
Freire et al. [61]
Male Wistar rats
Vaisy et al. [62]
Male Wistar rats
Cafeteria diet enriched with 2.5% of Cr
for 12 wk
Training: swimming
Male Wistar rats
Loading phase: Chow containing 13% of
Cr for 7d
+
Maintenance phase: Chow containing 2%
of Cr for 55 d
Training: high intensity treadmill running
Araújo et al. [60]
Main Findings
↓ plasma glucose levels during 1–4 wk
after Cr alone;
↓ plasma glucose levels during 1–8 wk
after Cr and exercise protocol.
↔ glucose uptake;
↔ glucose AUC during OGTT;
↔ liver and quadriceps glycogen content.
↔ fasting blood glucose concentration;
↓ fasting plasma insulin level after training
and training + creatine;
↓ whole body insulin level.
↔ glucose uptake;
↓ glucose AUC during OGTT after Cr and
exercise protocol.
Note: ↑: increase; ↓: decrease; ↔: no change; Cr: Creatine; PCr: phosphorylcreatine; TCr: total creatine; OGTT: oral glucose tolerance test;
AUC: area under the curve.
Op’t Eijnde et al. [9] provided new insights on the potential benefits of creatine plus
exercise on glucose metabolism in humans. In this study, healthy individuals had one
of their legs immobilized for two weeks, while they received either creatine (20 g·d−1 )
or placebo supplementation. After the immobilization period, participants underwent a
10-week knee extension training (3 times a week). The immobilization period caused a
significant reduction in GLUT-4 protein expression (−20%) in the control group, but not in
the creatine supplemented group. The rehabilitation period promoted a normalization of
the GLUT-4 content in the control group and a ~40% increase in GLUT-4 expression in the
creatine group. Additionally, rehabilitation training per se did not increase muscle GLUT4
content above the baseline levels, but creatine along with training led to a substantial
increase in this protein (+40%). Of relevance, the authors also reported that muscle glycogen
was significantly augmented only when exercise training was undertaken in conjunction
with creatine supplementation [9]. Using a similar experimental design, Derave et al. [63]
showed that creatine (15 g·d−1 during immobilization followed by 2.5 g·d−1 for 6 weeks
during rehabilitation) combined or not with protein supplementation was able to increase
GLUT-4 protein expression and improve oral glucose tolerance following a 6-week exercise
rehabilitation program that started two weeks after a single-leg immobilization protocol.
Gualano et al. [18] demonstrated that a 12-week creatine supplementation protocol
(20 g·d−1 for 10 days followed by 10 g·d−1 throughout the remaining period) associated
with moderate-intensity, aerobic exercise training (3 times a week) resulted in a greater
decrease in plasma glucose in response to oral glucose tolerance test, compared to exercise
alone, in sedentary but apparently healthy men. These data suggested a synergistic effect
of exercise and creatine on glucose tolerance; however, in this and other studies [16,33],
creatine did not change fasting insulin and Homeostatic Model Assessment for Insulin
Resistance (HOMA-IR), a surrogate of insulin resistance.
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Next to this preliminary study involving healthy participants, Gualano et al. [19]
conducted a small-scale, double-blind, placebo-controlled trial involving T2DM patients,
who underwent exercise training and received either creatine supplementation (5 g·d−1
for 12 weeks) or placebo. In this study, creatine supplementation along with exercise
training significantly reduced glycated hemoglobin (HbA1c) and glycemia in response to
a meal tolerance test. No significant differences were observed for insulin and C-peptide
concentrations. The beneficial effect on glycemic control was partially explained by an
improvement in GLUT-4 translocation to sarcolemma, rather than in total muscle GLUT-4
content [19]. In an ancillary analysis from this study, decreased HbA1c levels and increased
GLUT-4 translocation were associated with increased AMPK protein expression [38], providing new insights on the molecular mechanisms underlying the effects of combined
creatine and exercise interventions on glucose metabolism. Of clinical relevance, creatine
supplementation as an adjuvant therapy appeared to be safe, as no adverse events were
reported and no alterations in health-related laboratory markers were seen [19,38].
However, the efficacy of creatine supplementation was not confirmed by a subsequent
randomized, double-blind, placebo-controlled, pilot trial involving community-dwelling
older adults [64]. After a 12-week follow-up period, creatine supplementation (5 g·d−1 )
and resistance training (3 times a week) did not improve insulin resistance (assessed by
fasting blood glucose and insulin, and HOMA-IR). It is possible to speculate that the better
glycemic control exhibited by the participants in this study, compared to those of Gualano
et al.’s study, may partially explain the null findings on the basis of a “ceiling effect”. The
studies assessing the effect of creatine supplementation along exercise on glycemic control
in humans are summarized in Table 4.
Table 4. Effect of creatine supplementation along with exercise on glucose metabolism in humans.
Reference
Op’t Eijnde et al. [9]
Derave et al. [63]
Sample (n)
Young, healthy
subjects (22)
Young, healthy
subjects (22)
Study Design
Double-blind
placebo-controlled trial
Double-blind,
placebo-controlled
trial
Creatine and Training
Protocol
Loading phase:
20 g·d−1 during
immobilization period
(2 wk)
+
Maintenance phase:
15 g·d−1 for 3 wk
followed by 5 g·d−1 for
7 wk during
rehabilitation training
Program training:
knee-extensor
resistance training
(3 times·wk−1 )
Loading phase:
15 g·d−1 during
immobilization period
(2 wk) combined or not
with protein
supplementation
+
Maintenance phase:
2.5 g·d−1 for 6 wk
during rehabilitation
training
Program training:
knee-extensor
resistance training
(3 times·wk−1 )
Main Findings
Immobilization period:
↓ 20% GLUT-4 in placebo
group, but not in Cr group;
↔ glycogen and Cr muscle
content in both groups.
Rehabilitation period:
↑ 40% GLUT-4 in Cr group;
↑ glycogen and Cr muscle
content after Cr.
Immobilization period:
↓ GLUT-4 in placebo and Cr
group, but not in Cr + protein
group;
↔ glycogen and Cr muscle
content in all groups.
Rehabilitation period:
↑ 24% GLUT-4 in Cr group and
↑ 33% in Cr + protein group;
↑ glycogen and Cr muscle
content after Cr and Cr +
protein supplementation.
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Table 4. Cont.
Reference
Gualano et al. [18]
Gualano et al. [19]
Sample (n)
Healthy,
sedentary male
(22)
T2DM patients
(25)
Alves et al. [38]
T2DM patients
(25)
Oliveira et al. [64]
Healthy, older
adults (32)
Study Design
Creatine and Training
Protocol
Main Findings
Double-blind,
randomized-placebocontrolled
trial
Loading phase:
0.3 g·kg−1 ·d−1 of Cr
for 1 wk
+
Maintenance phase:
0.15 g·kg−1 ·d−1 for
11 wk
Program training:
aerobic training at 70%
of the VO2 max
↓ glucose AUC after OGTT;
↔ fasting insulin;
↔ HOMA-IR.
Double-blind,
randomized-placebocontrolled
trial
5
of Cr for 12 wk
Program training:
Aerobic training and
resistance training
↓ HbA1c in Cr group;
↓ glycemia during MTT (0, 30
and 60 min) in Cr group;
↑ muscle PCr content in Cr
group;
↑ muscle strength and function
in Cr group
Double-blind,
randomized-placebocontrolled
trial
randomized,
double-blind,
placebo-controlled,
parallel-group
clinical trial
5 g·d−1 of Cr for 12 wk
Program training:
Aerobic training and
resistance training
↑ AMPK protein expression;
↔ IR-β, Akt1 and MAPK.
5 g·d−1 of Cr for 12 wk
Program training:
resistance training
↔ inflammatory biomarkers
↔ fasting blood glucose;
↔ fasting insulin;
↔ HOMA-IR.
g ·d−1
Note: ↑: increase; ↓: decrease; ↔: no change; Cr: Creatine; PCr: phosphorylcreatine; TCr: total creatine; OGTT: oral glucose tolerance test;
GLUT-4: glucose transporter; T2DM: type 2 diabetes mellitus; AUC: area under the curve; HOMA-IR: Homeostatic Model Assessment for
Insulin Resistance; HbA1c: glycosylated hemoglobin; IR-β: insulin receptor; Akt1: protein kinase B; MAPK: AMP-activated protein kinase.
5. Conclusions and Future Directions
Creatine supplementation has the potential to promote changes in glucose metabolism
that may favor a healthier metabolic profile. This may be particularly true when exercise training is provided along with this supplement, as creatine seems to enhance the
training adaptations.
Evidence supporting the role of creatine on glucose metabolism remains speculative.
As discussed, pre-clinical data are difficult to interpret as creatine responses are highly
dependent on the experimental model adopted. The few existing clinical trials are smallscale, short-term and, therefore, exploratory. Despite the fact that a few of them have
revealed promising benefits of creatine on glucose control, especially when exercise as
co-prescribed, further large, longer-term, controlled trials involving T2DM with variable
disease severity and under different pharmacological treatments are necessary to drawn
firm conclusions on the efficacy and safety of creatine as an anti-diabetic intervention. It
is equally important to develop new investigations aimed at unraveling the mechanisms
by which creatine, aligned or not with training, could regulate glucose control, as basic
research is indeed useful to better target potentially most benefited populations for testing
creatine in next clinical trials.
Author Contributions: Conceptualization, M.Y.S., G.G.A. and B.G.; writing—original draft preparation, M.Y.S., G.G.A. and B.G.; writing—review and editing, M.Y.S., G.G.A. and B.G.; visualization,
M.Y.S., G.G.A. and B.G.; supervision, B.G. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no specific funding.
Nutrients 2021, 13, 570
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Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Guilherme Giannini Artioli and Bruno Gualano were supported by FAPESP
#2019/25032-9 and 2017/12511-0, respectively.
Conflicts of Interest: BG has received research grants, creatine donation for scientific studies, travel
support for participation in scientific conferences and honorarium for speaking at lectures from
AlzChem (a company which manufactures creatine). Additionally, he serves as a member of the
Scientific Advisory Board for Alzchem. The others have no conflict of interests.
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